Thesis (PhD)--Stellenbosch University, 2012. / ENGLISH ABSTRACT: Background: Myocardial oxidative fuel supply is increased in obese conditions. How
this metabolic environment and altered cardiometabolic phenotype associated with prediabetic
obesity impacts on cardiac function and tolerance to ischaemia/reperfusion
injury remains uncertain. While obese individuals are likely to be treated with PPARα
agonists, controversy exists as to how activation of the PPARα receptor influences
cardiovascular function and post-ischaemic recovery. Aims: To determine in a model of
hyperphagia-induced obesity 1) whether protracted obesity is associated with left
ventricular (LV) mechanical dysfunction; 2) the responsiveness of these hearts to insulin
stimulation; 3) whether insulin can afford cardioprotection against ischaemia/reperfusion
damage; and 4) how obesity and chronic PPARα agonist (K-111) treatment influences
myocardial function, substrate metabolism, mitochondrial function and post-ischaemic
outcomes.
Methods: Male Wistar rats were fed standard rat chow or a high caloric diet. 1) In vivo
LV mechanical function was assessed echocardiographically in 32 week fed animals. Ex
vivo LV function was measured in the presence of glucose, insulin and/or fatty acid (FA);
2) Ex vivo myocardial insulin sensitivity was assessed by measuring insulin stimulated
glycolytic flux in 16 week fed rats. Insulin was also administered prior to and during
regional ischaemia to determine its effect on post-ischaemic function and infarct size; 3)
K-111 was added to the drinking water during the last 10 weeks of feeding (feeding
period of 18 weeks); a) Ventricular mitochondrial function was determined
polarographically in the presence of either glutamate or palmitoyl-L-carnitine as
substrates; b) Myocardial carbohydrate and lipid metabolism, and in a separate series of perfusions, myocardial infarct size were determined in the presence of physiological or
high insulin (30 or 50μIU/ml) and FA (0.7 or 1.5mM) concentrations.
Results: 1) Obese animals maintained normal in vivo LV mechanical function. Glucose
perfused hearts from obese animals had depressed aortic outputs compared to the
control group (32.58±1.2 vs. 46.17±0.91 ml/min; p<0.001) which was abolished by the
presence of FA; 2) Hearts from obese animals had reduced insulin stimulated glycolytic
flux rates (1.54±0.42 vs. 2.16±0.57 μmol/g ww/min, p<0.01). Although insulin reduced
infarct size in the obese group (20.94±1.60 vs. 41.67±2.09 %, p<0.001), its
cardioprotective effect was attenuated in the presence of FA; 3) By simulating the in vivo
metabolic environment of control and obese animals in ex vivo perfusions, elevated
insulin and FA levels associated with obesity increased infarct sizes in the obese group
compared to the control group (47.44±3.13 vs. 37.17±2.63 %, p<0.05); 4) While chronic
K-111 treatment reversed systemic metabolic abnormalities associated with obesity,
neither obesity nor the drug influenced myocardial and mitochondrial function or postischaemic
outcomes. K-111 was able to reduce palmitate oxidation in the obese group.
Conclusion: Elevated levels of circulating FFA may be important in maintaining normal
LV mechanical function in the obese condition. While obesity had no impact on
myocardial mitochondrial function and post-ischaemic outcomes during comparable
perfusion conditions, the specific metabolic environment associated with obesity may
augment post-ischaemic injury. K-111 is effective in reducing obesity related metabolic
abnormalities, but has no effects on myocardial function, mitochondrial function or
ischaemic tolerance. / AFRIKAANSE OPSOMMING: Agtergrond: Miokardiale oksidatiewe substraat voorsiening is verhoog in vetsug. Hoe
hierdie metaboliese omgewing en veranderde miokardiale metaboliese fenotipe in prediabetiese
vetsug miokardiale funksie en iskemie/herperfusie skade beïnvloed, is
onseker. Alhoewel vetsugtige individue met PPARα agoniste behandel kan word, is die
resultate verkry van hierdie reseptor aktivering op miokardiale funksie en iskemiese
skade teenstrydig.
Doelwitte: Om te bepaal of 1) verlengde vetsug linker ventrikulêre (LV) funksie
beïnvloed; 2) hierdie harte sensitief vir insulien stimulasie is; 3) insulien die hart teen
iskemie/herperfusie beskadiging beskerm; en of 4) vetsug en chroniese K-111
behandeling miokardiale funksie, substraat metabolisme, mitochondriale funksie en
post-iskemiese herstel in vetsugtige, insulienweerstandige rotte beïnvloed.
Metodes: Manlike Wistar rotte is met gewone rotkos, of ʼn hoé kalorie dieet gevoer. 1) In
vivo LV funksie in 32 week gevoerde rotte is met behulp van eggokardiografie bepaal.
Ex vivo LV funksie is met of sonder insulien en/of vetsure in die perfusaat bepaal; 2) Die
ex vivo insuliensensitiwiteit is in 16 weke gevoerde rotte bepaal deur miokardiale
glikolise te meet. Insulien is ook voor en tydens streeksiskemie toegedien, ten einde sy
effek op miokardiale beskerming te bepaal; 3) K-111 is in die drink water van rotte
toegedien vir die laaste 10 weke van hul dieet (voedingsperiode van 18 weke); a)
Ventrikulêre mitochondriale funksie is polarografies bepaal in die aanwesigheid van
glutamaat of palmitiel-L-karnitien; b) Miokardiale koolhidraat- en lipied metabolisme, en
in ʼn aparte groep rotte, infarktgrootte, is bepaal in die teenwoordigheid van fisiologiese
of hoë insulien- (30 of 50μIU/ml) en vetsuurvlakke (0.7 of 1.5mM).
Resultate: 1) Vetsugtige rotte het normale in vivo LV funksie gehandhaaf. Glukose
geperfuseerde harte van vet rotte se LV funksie was laer as die van kontroles (Aorta
omset: 32.58±1.2 vs. 46.17±0.91 ml/min; p<0.001), maar dit het verbeter in
teenwoordigheid van vetsure; 2) Harte van vetsugtige rotte het verlaagde insuliengestimuleerde
glikolise getoon (1.54±0.42 vs. 2.16±0.57 μmol/g ww/min, p<0.01).
Alhoewel insulien infarktgrootte in die vetsugtige groep verlaag het (20.94±1.60 vs.
41.67±2.09 %, p<0.001), is sy beskermende effekte in die teenwoordigheid van vetsure
verlaag; 3) deur die in vivo metaboliese omgewing van kontrole en vetsugtige rotte in die
perfusaat van die harte ex vivo te simuleer, is dit aangetoon dat die verhoogde vlakke
van insulien en vetsure, geassosieer met vetsugtigheid, infarktgroottes in die vetsugtige
groep teenoor die kontrole groep verhoog het (47.44±3.13 vs 37.17±2.63 %, p<0.05); 4)
Hoewel chroniese gebruik van K-111 die metaboliese abnormaliteite gepaardgaande
met vetsug normaliseer het, het beide vetsug en die middel geen invloed op miokardiale
of mitochondriale funksie of vatbaarheid vir iskemiese beskadiging gehad nie. K-111 het
miokardiale palmitaatoksidasie in die vetsugtige behandelde groep verlaag.
Gevolgtrekking: Verhoogde bloed vetsuurvlakke in vetsug mag n belangrike rol in die
handhawing van sistoliese funksie speel. Dit blyk dat die spesifieke in vivo omgewing
geassosieer met vetsug wel tot verhoogte vatbaarheid vir iskemie/herperfusie skade
mag lei. K-111 is effektief om die sistemiese metaboliese abnormaliteite gepaard met
vetsugtigheid te verbeter, maar het geen effek op miokardiale funksie, mitochondriale
funksie of vatbaarheid vir iskemie gehad nie.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:sun/oai:scholar.sun.ac.za:10019.1/20351 |
| Date | 03 1900 |
| Creators | Smith, Wayne |
| Contributors | Du Toit, E. F., Lochner, A., Stellenbosch University. Faculty of Health Sciences. Dept. of Biomedical Sciences. Medical Physiology. |
| Publisher | Stellenbosch : Stellenbosch University |
| Source Sets | South African National ETD Portal |
| Language | en_ZA |
| Detected Language | English |
| Type | Thesis |
| Format | 314 p. : ill. |
| Rights | Stellenbosch University |
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